The Mre11/Rad50/Nbs1 complex (MRN) plays critical roles in the maintenance of genome stability. Both NBS and ATLD patient cells show increased chromosomal translocation in blood cells, but the mechanisms are not clear. In this revision application, we will use newly established translocation assay systems to study the role of MRN in the prevention of chromosomal translocation. We will investigate what functions of MRN are important for the prevention of chromosomal translocation. We will analyze translocation junctions when translocations are induced by different mechanisms. We will study the role of MRN in the repair of DSBs upon replication stress and link this function of MRN with its role in the prevention of chromosome translocation. Clarifying the role of MRN in the prevention of chromosomal translocation will significantly help elucidate the translocation mechanisms, which is of great importance to the understanding of cancer etiology. These studies will also help develop therapeutic interventions to prevent de novo and therapy-related cancers that are associated with chromosomal translocations. PUBLIC HEALTH RELEVANCE: Chromosomal translocations are highly associated with cancer development. Both Nbs1 (Nijmegen breakage syndrome) and Mre11 (ataxia-telangiectasia-like disorder) deficient patients exhibit increased level of chromosomal translocations and higher risk of developing lymphoid tumors. Understanding the role of the Mre11/Rad50/Nbs1 complex in the prevention of chromosomal translocation will shed light on the cellular mechanisms to maintain genome stability and will ultimately help develop therapeutic interventions for preventing cancers. This revision application is in response to the NIH announcement of the Availability of Recovery Act Funds. We will mainly use the budget to create new jobs.